India Allele Finder: a web-based annotation tool for identifying common alleles in next-generation sequencing data of Indian origin.

BMC Res Notes. 2017 Jun 27;10(1):233

Authors: Zhang JF, James F, Shukla A, Girisha KM, Paciorkowski AR

Abstract
OBJECTIVE: We built India Allele Finder, an online searchable database and command line tool, that gives researchers access to variant frequencies of Indian Telugu individuals, using publicly available fastq data from the 1000 Genomes Project. Access to appropriate population-based genomic variant annotation can accelerate the interpretation of genomic sequencing data. In particular, exome analysis of individuals of Indian descent will identify population variants not reflected in European exomes, complicating genomic analysis for such individuals.
RESULTS: India Allele Finder offers improved ease-of-use to investigators seeking to identify and annotate sequencing data from Indian populations. We describe the use of India Allele Finder to identify common population variants in a disease quartet whole exome dataset, reducing the number of candidate single nucleotide variants from 84 to 7. India Allele Finder is freely available to investigators to annotate genomic sequencing data from Indian populations. Use of India Allele Finder allows efficient identification of population variants in genomic sequencing data, and is an example of a population-specific annotation tool that simplifies analysis and encourages international collaboration in genomics research.

PMID: 28655339 [PubMed - in process]

A missense variant in FGD6 confers increased risk of polypoidal choroidal vasculopathy.

Nat Genet. 2016 Jun;48(6):640-7

Authors: Huang L, Zhang H, Cheng CY, Wen F, Tam PO, Zhao P, Chen H, Li Z, Chen L, Tai Z, Yamashiro K, Deng S, Zhu X, Chen W, Cai L, Lu F, Li Y, Cheung CM, Shi Y, Miyake M, Lin Y, Gong B, Liu X, Sim KS, Yang J, Mori K, Zhang X, Cackett PD, Tsujikawa M, Nishida K, Hao F, Ma S, Lin H, Cheng J, Fei P, Lai TY, Tang S, Laude A, Inoue S, Yeo IY, Sakurada Y, Zhou Y, Iijima H, Honda S, Lei C, Zhang L, Zheng H, Jiang D, Zhu X, Wong TY, Khor CC, Pang CP, Yoshimura N, Yang Z

Abstract
Polypoidal choroidal vasculopathy (PCV), a subtype of 'wet' age-related macular degeneration (AMD), constitutes up to 55% of cases of wet AMD in Asian patients. In contrast to the choroidal neovascularization (CNV) subtype, the genetic risk factors for PCV are relatively unknown. Exome sequencing analysis of a Han Chinese cohort followed by replication in four independent cohorts identified a rare c.986A>G (p.Lys329Arg) variant in the FGD6 gene as significantly associated with PCV (P = 2.19 × 10(-16), odds ratio (OR) = 2.12) but not with CNV (P = 0.26, OR = 1.13). The intracellular localization of FGD6-Arg329 is distinct from that of FGD6-Lys329. In vitro, FGD6 could regulate proangiogenic activity, and oxidized phospholipids increased expression of FGD6. FGD6-Arg329 promoted more abnormal vessel development in the mouse retina than FGD6-Lys329. Collectively, our data suggest that oxidized phospholipids and FGD6-Arg329 might act synergistically to increase susceptibility to PCV.

PMID: 27089177 [PubMed - indexed for MEDLINE]

Emergence of MET hyper-amplification at progression to MET and BRAF inhibition in colorectal cancer.

Br J Cancer. 2017 Jun 27;:

Authors: Oddo D, Siravegna G, Gloghini A, Vernieri C, Mussolin B, Morano F, Crisafulli G, Berenato R, Corti G, Volpi CC, Buscarino M, Niger M, Dunne PD, Rospo G, Valtorta E, Bartolini A, Fucà G, Lamba S, Martinetti A, Di Bartolomeo M, de Braud F, Bardelli A, Pietrantonio F, Di Nicolantonio F

Abstract
BACKGROUND: Combined MET and BRAF inhibition showed clinical benefit in a patient with rectal cancer carrying BRAF(V600E) and MET amplification. However after 4 months, acquired resistance emerged and the patient deceased shortly after disease progression. The mechanism of resistance to this drug combination is unknown.
METHODS: We analysed plasma circulating tumour DNA obtained at progression by exome sequencing and digital PCR. MET gene and mRNA in situ hybridisation analyses in two bioptic specimens obtained at progression were used to confirm the plasma data.
RESULTS: We identified in plasma MET gene hyper-amplification as a potential mechanism underlying therapy resistance. Increased MET gene copy and transcript levels were detected in liver and lymph node metastatic biopsies. Finally, transduction of MET in BRAF mutant colorectal cancer cells conferred refractoriness to BRAF and MET inhibition.
CONCLUSIONS: We identified in a rectal cancer patient MET gene hyper-amplification as mechanism of resistance to dual BRAF and MET inhibition.British Journal of Cancer advance online publication, 27 June 2017; doi:10.1038/bjc.2017.196 www.bjcancer.com.

PMID: 28654634 [PubMed - as supplied by publisher]

Extension of the phenotype of biallelic loss-of-function mutations in SLC25A46 to the severe form of pontocerebellar hypoplasia type I.

Clin Genet. 2017 Jun 27;:

Authors: Braunisch MC, Gallwitz H, Abicht A, Diebold I, Holinski-Feder E, Van Maldergem L, Lammens M, Kovács-Nagy R, Alhaddad B, Strom TM, Meitinger T, Senderek J, Rudnik-Schöneborn S, Haack TB

Abstract
Biallelic mutations in SLC25A46, encoding a modified solute transporter involved in mitochondrial dynamics, have been identified in a wide range of conditions such as hereditary motor and sensory neuropathy with optic atrophy type VIB (OMIM: *610826) and congenital lethal pontocerebellar hypoplasia (PCH). To date, 18 patients from 13 families have been reported, presenting with the key clinical features of optic atrophy, peripheral neuropathy, and cerebellar atrophy. The course of the disease was highly variable ranging from severe muscular hypotonia at birth and early death to first manifestations in late childhood and survival into the fifties. Here we report on four patients from two families diagnosed with pontocerebellar hypoplasia (PCH) who died within the first month of life from respiratory insufficiency. Patients from one family had pathoanatomically proven spinal motor neuron degeneration (PCH1). Using exome sequencing, we identified biallelic disease-segregating loss-of-function mutations in SLC25A46 in both families. Our study adds to the definition of the SLC25A46-associated phenotypic spectrum that includes neonatal fatalities due to PCH as the severe extreme.

PMID: 28653766 [PubMed - as supplied by publisher]

Development of Kras mutant lung adenocarcinoma in mice with knockout of the airway lineage-specific gene Gprc5a.

Int J Cancer. 2017 Jun 27;:

Authors: Fujimoto J, Nunomura-Nakamura S, Liu Y, Lang W, McDowell T, Jakubek Y, Ezzeddine D, Ochieng JK, Petersen J, Davies G, Fukuoka J, Wistuba II, Ehli E, Fowler J, Scheet P, Kadara H

Abstract
Despite the urgency for prevention and treatment of lung adenocarcinoma (LUAD), we still do not know drivers in pathogenesis of the disease. Earlier work revealed that mice with knockout of the G-protein coupled receptor Gprc5a develop late onset lung tumors including LUADs. Here, we sought to further probe the impact of Gprc5a expression on LUAD pathogenesis. We first surveyed GPRC5A expression in human tissues and found that GPRC5A was markedly elevated in human normal lung relative to other normal tissues and was consistently down-regulated in LUADs. In sharp contrast to wild type littermates, Gprc5a(-/-) mice treated chronically with the nicotine-specific carcinogen NNK developed LUADs by six months following NNK exposure. Immunofluorescence analysis revealed that the LUADs exhibited abundant expression of surfactant protein C and lacked the clara cell marker Ccsp, suggesting that these LUADs originated from alveolar type II cells. Next, we sought to survey genome-wide alterations in the pathogenesis of Gprc5a(-/-) LUADs. Using whole exome sequencing, we found that carcinogen-induced LUADs exhibited markedly higher somatic mutation burdens relative to spontaneous tumors. All LUADs were found to harbor somatic mutations in the Kras oncogene (p. G12D or p. Q61R). In contrast to spontaneous lesions, carcinogen-induced Gprc5a(-/-) LUADs exhibited mutations (variants and copy number gain) in additional drivers (Atm, Kmt2d, Nf1, Trp53, Met, Ezh2). Our study underscores genomic alterations that represent early events in the development of Kras mutant LUAD following Gprc5a loss and tobacco carcinogen exposure and that may constitute targets for prevention and early treatment of this disease. This article is protected by copyright. All rights reserved.

PMID: 28653505 [PubMed - as supplied by publisher]

Newborn Sequencing in Genomic Medicine and Public Health.

Pediatrics. 2017 Feb;139(2):

Authors: Berg JS, Agrawal PB, Bailey DB, Beggs AH, Brenner SE, Brower AM, Cakici JA, Ceyhan-Birsoy O, Chan K, Chen F, Currier RJ, Dukhovny D, Green RC, Harris-Wai J, Holm IA, Iglesias B, Joseph G, Kingsmore SF, Koenig BA, Kwok PY, Lantos J, Leeder SJ, Lewis MA, McGuire AL, Milko LV, Mooney SD, Parad RB, Pereira S, Petrikin J, Powell BC, Powell CM, Puck JM, Rehm HL, Risch N, Roche M, Shieh JT, Veeraraghavan N, Watson MS, Willig L, Yu TW, Urv T, Wise AL

Abstract
The rapid development of genomic sequencing technologies has decreased the cost of genetic analysis to the extent that it seems plausible that genome-scale sequencing could have widespread availability in pediatric care. Genomic sequencing provides a powerful diagnostic modality for patients who manifest symptoms of monogenic disease and an opportunity to detect health conditions before their development. However, many technical, clinical, ethical, and societal challenges should be addressed before such technology is widely deployed in pediatric practice. This article provides an overview of the Newborn Sequencing in Genomic Medicine and Public Health Consortium, which is investigating the application of genome-scale sequencing in newborns for both diagnosis and screening.

PMID: 28096516 [PubMed - indexed for MEDLINE]

Deficiency of WARS2, encoding mitochondrial tryptophanyl tRNA synthetase, causes severe infantile onset leukoencephalopathy.

Am J Med Genet A. 2017 Jun 26;:

Authors: Theisen BE, Rumyantseva A, Cohen JS, Alcaraz WA, Shinde DN, Tang S, Srivastava S, Pevsner J, Trifunovic A, Fatemi A

Abstract
Pathogenic variants in the mitochondrial aminoacyl tRNA synthetases lead to deficiencies in mitochondrial protein synthesis and are associated with a broad range of clinical presentations usually with early onset and inherited in an autosomal recessive manner. Of the 19 mitochondrial aminoacyl tRNA synthetases, WARS2, encoding mitochondrial tryptophanyl tRNA synthetase, was as of late the only one that had not been associated with disease in humans. A case of a family with pathogenic variants in WARS2 that caused mainly intellectual disability, speech impairment, aggressiveness, and athetosis was recently reported. Here we substantially extend and consolidate the symptomatology of WARS2 by presenting a patient with severe infantile-onset leukoencephalopathy, profound intellectual disability, spastic quadriplegia, epilepsy, microcephaly, short stature, failure to thrive, cerebral atrophy, and periventricular white matter abnormalities. He was found by whole-exome sequencing to have compound heterozygous variants in WARS2, c.938A>T (p.K313M) and c.298_300delCTT (p.L100del). De novo synthesis of proteins inside mitochondria was reduced in the patient's fibroblasts, leading to significantly lower steady-state levels of respiratory chain subunits compared to control and resulting in lower oxygen consumption rates.

PMID: 28650581 [PubMed - as supplied by publisher]

The genetics of platelet count and volume in humans.

Platelets. 2017 Jun 26;:1-6

Authors: Eicher JD, Lettre G, Johnson AD

Abstract
The last decade has witnessed an explosion in the depth, variety, and amount of human genetic data that can be generated. This revolution in technical and analytical capacities has enabled the genetic investigation of human traits and disease in thousands to now millions of participants. Investigators have taken advantage of these advancements to gain insight into platelet biology and the platelet's role in human disease. To do so, large human genetics studies have examined the association of genetic variation with two quantitative traits measured in many population and patient based cohorts: platelet count (PLT) and mean platelet volume (MPV). This article will review the many human genetic strategies-ranging from genome-wide association study (GWAS), Exomechip, whole exome sequencing (WES), to whole genome sequencing (WGS)-employed to identify genes and variants that contribute to platelet traits. Additionally, we will discuss how these investigations have examined and interpreted the functional implications of these newly identified genetic factors and whether they also impart risk to human disease. The depth and size of genetic, phenotypic, and other -omic data are primed to continue their growth in the coming years and provide unprecedented opportunities to gain critical insights into platelet biology and how platelets contribute to disease.

PMID: 28649937 [PubMed - as supplied by publisher]

Novel 25 kb Deletion of MERTK Causes Retinitis Pigmentosa With Severe Progression.

Invest Ophthalmol Vis Sci. 2017 Mar 01;58(3):1736-1742

Authors: Evans DR, Green JS, Johnson GJ, Schwartzentruber J, Majewski J, Beaulieu CL, Qin W, Marshall CR, Paton TA, Roslin NM, Paterson AD, Fahiminiya S, French J, Boycott KM, Woods MO, FORGE Canada Consortium

Abstract
Purpose: Retinitis pigmentosa (RP) describes a complex group of inherited retinal dystrophies with almost 300 reported genes and loci. We investigated the genetic etiology of autosomal recessive RP (arRP) in a large kindred with 5 affected family members, who reside on the island of Newfoundland, Canada.
Methods: Genetic linkage analysis was performed on 12 family members (Infinium HumanOmni2.5-8 BeadChip). Whole exome sequencing analysis (Illumina HiSeq) was performed on one affected individual. A custom pipeline was applied to call, annotate, and filter variants. FishingCNV was used to scan the exome for rare copy number variants (CNVs). Candidate CNVs subsequently were visualized from microarray data (CNVPartition v.3.1.6.). MERTK breakpoints were mapped and familial cosegregation was tested using Sanger Sequencing.
Results: We found strong evidence of linkage to a locus on chromosome 2 (logarithm of the odds [LOD] 4.89 [θ = 0]), at an interval encompassing the MERTK gene. Whole exome sequencing did not uncover candidate point mutations in MERTK, or other known RP genes. Subsequently, CNV analysis of the exome data and breakpoint mapping revealed a 25,218 bp deletion of MERTK, encompassing exons 6 to 8, with breakpoints in introns 5 (chr2:112,725,292) and 8 (chr2:112,750,421). A 48 bp insertion sequence was buried within the breakpoint; 18 bps shared homology to MIR4435-2HG and LINC00152, and 30 bp mapped to MERTK. The deletion cosegregated with arRP in the family.
Conclusions: This study describes the molecular and clinical characterization of an arRP family segregating a novel 25 kb deletion of MERTK. These findings may assist clinicians in providing a diagnosis for other unsolved RP cases.

PMID: 28324114 [PubMed - indexed for MEDLINE]

Discovery and characterization of spontaneous mouse models of craniofacial dysmorphology.

Dev Biol. 2016 Jul 15;415(2):216-227

Authors: Palmer K, Fairfield H, Borgeia S, Curtain M, Hassan MG, Dionne L, Yong Karst S, Coombs H, Bronson RT, Reinholdt LG, Bergstrom DE, Donahue LR, Cox TC, Murray SA

Abstract
Craniofacial abnormalities are among the most common features of human genetic syndromes and disorders. The etiology of these conditions is often complex, influenced by both genetic context and the environment. Frequently, craniofacial abnormalities present as part of a syndrome with clear comorbid phenotypes, providing additional insight into mechanisms of the causative gene or pathway. The mouse has been a key tool in our understanding of the genetic mechanisms of craniofacial development and disease, and can provide excellent models for human craniofacial abnormalities. While powerful genetic engineering tools in the mouse have contributed significantly our understanding of craniofacial development and dysmorphology, forward genetic approaches provide an unbiased means to identify new genes and pathways. Moreover, spontaneous mutations can occur on any number of genetic backgrounds, potentially revealing critical genes that require a specific genetic context. Here we report discovery and phenotyping of 43 craniofacial mouse models, derived primarily from a screen for spontaneous mutations in production colonies at the Jackson Laboratory. We identify the causative gene for 33 lines, including novel genes in pathways not previously connected to craniofacial development, and novel alleles of known genes that present with unique phenotypes. Together with our detailed characterization, this work provides a valuable gene discovery resource for the craniofacial community, and a rich source of mouse models for further investigation.

PMID: 26234751 [PubMed - indexed for MEDLINE]

Genotype-phenotype evaluation of MED13L defects in the light of a novel truncating and a recurrent missense mutation.

Eur J Med Genet. 2017 Jun 20;:

Authors: Asadollahi R, Zweier M, Gogoll L, Schiffmann R, Sticht H, Steindl K, Rauch A

Abstract
A decade after the designation of MED13L as a gene and its link to intellectual disability (ID) and dextro-looped transposition of great arteries in 2003, we previously described a recognizable syndrome due to MED13L haploinsufficiency. Subsequent reports of 22 further patients diagnosed by genome-wide testing further delineated the syndrome with expansion of the phenotypic spectrum and showed reduced penetrance for congenital heart defects. We now report two novel patients identified by whole exome sequencing, one with a de novo MED13L truncating mutation and the other with a de novo missense mutation. The first patient indicates some facial resemblance to Kleefstra syndrome as a novel differential diagnosis, and the second patient shows, for the first time, recurrence of a MED13L missense mutation (p.(Asp860Gly)). Notably, our in silico modelling predicted this missense mutation to decrease the stability of an alpha-helix and thereby affecting the MED13L secondary structure, while the majority of published missense mutations remain variants of uncertain significance. Review of the reported patients with MED13L haploinsufficiency indicates moderate to severe ID and facial anomalies in all patients, as well as severe speech delay and muscular hypotonia in the majority. Further common signs include abnormal MRI findings of myelination defects and abnormal corpus callosum, ataxia and coordination problems, autistic features, seizures/abnormal EEG, or congenital heart defects, present in about 20-50% of the patients. With reference to facial anomalies, the majority of patients were reported to show broad/prominent forehead, low set ears, bitemporal narrowing, upslanting palpebral fissures, depressed/flat nasal bridge, bulbous nose, and abnormal chin, but macroglossia and horizontal eyebrows were also observed in ∼30%. The latter are especially important in the differential diagnosis of 1p36 deletion and Kleefstra syndromes, while the more common facial gestalt shows some resemblance to 22q11.2 deletion syndrome. Despite the fact that MED13L was found to be one of the most common ID genes in the Deciphering Developmental Disorders Study, further detailed patient descriptions are needed to explore the full clinical spectrum, potential genotype-phenotype correlations, as well as the role of missense mutations and potential mutational hotspots along the gene.

PMID: 28645799 [PubMed - as supplied by publisher]

Defective mitochondrial RNA processing due to PNPT1 variants causes Leigh syndrome.

Hum Mol Genet. 2017 Jun 22;:

Authors: Matilainen S, Carroll CJ, Richter U, Euro L, Pohjanpelto M, Paetau A, Isohanni P, Suomalainen A

Abstract
Leigh syndrome is a severe infantile encephalopathy with an exceptionally variable genetic background. We studied the exome of a child manifesting with Leigh syndrome at one month of age and progressing to death by the age of 2.4 years, and identified novel compound heterozygous variants in PNPT1, encoding the polynucleotide phosphorylase (PNPase). Expression of the wild type PNPT1 in the subject's myoblasts functionally complemented the defects, and the pathogenicity was further supported by structural predictions and protein and RNA analyses. PNPase is a key enzyme in mitochondrial RNA metabolism, with suggested roles in mitochondrial RNA import and degradation. The variants were predicted to locate in the PNPase active site and disturb the RNA processing activity of the enzyme. The PNPase trimer formation was not affected, but specific RNA processing intermediates derived from mitochondrial transcripts of the ND6 subunit of Complex I, as well as small mRNA fragments, accumulated in the subject's myoblasts. Mitochondrial RNA processing mediated by the degradosome consisting of hSUV3 and PNPase is poorly characterized, and controversy on the role and location of PNPase within human mitochondria exists. Our evidence indicates that PNPase activity is essential for correct maturation of the ND6 transcripts, and likely for the efficient removal of degradation intermediates. Loss of its activity will result in combined respiratory chain deficiency, and a classic respiratory chain-deficiency-associated disease, Leigh syndrome, indicating an essential role for the enzyme for normal function of the mitochondrial respiratory chain.

PMID: 28645153 [PubMed - as supplied by publisher]

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(exome OR "exome sequencing") AND disease

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12 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

(exome OR "exome sequencing") AND disease

These pubmed results were generated on 2017/06/22

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ALPK3 GENE MUTATION IN A PATIENT WITH CONGENITAL CARDIOMYOPATHY AND DYSMORPHIC FEATURES.

Cold Spring Harb Mol Case Stud. 2017 Jun 19;:

Authors: Cağlayan AO, Sezer RG, Kaymakcalan H, Ulgen E, Yavuz T, Baranoski JF, Bozaykut A, Serin Harmanci A, Yalcin Y, Youngblood MW, Yasuno K, Bilguvar K, Gunel M

Abstract
Primary cardiomyopathy is one of the most common inherited cardiac diseases and harbors significant phenotypic and genetic heterogeneity. Because of this, genetic testing has become standard in treatment of this disease group. Indeed, in recent years, next-generation DNA sequencing has found broad applications in medicine, both as a routine diagnostic tool for genetic disorders and also as a high-throughput discovery tool for identifying novel disease causing genes. We describe a male infant with primary dilated cardiomyopathy that was diagnosed using intrauterine echocardiography, and found to progress to hypertrophic cardiomyopathy after birth. This proband was born to a non-consanguineous family with a past history of a male fetus that died due to cardiac abnormalities at 30 weeks of gestation. Using whole-exome sequencing, a novel homozygous frameshift mutation (c.2018delC; p.Gln675SerfsX30) in ALPK3 was identified and confirmed with Sanger sequencing. Heterozygous family members were normal with echocardiographic examination. To date, only two studies have reported homozygous pathogenic variants of ALPK3, with a total of seven affected individuals with cardiomyopathy from four unrelated consanguineous families. We include a discussion of the patient's phenotypic features and a review of relevant literature findings.

PMID: 28630369 [PubMed - as supplied by publisher]

Novel NBAS mutations and fever-related recurrent acute liver failure in Chinese children: a retrospective study.

BMC Gastroenterol. 2017 Jun 19;17(1):77

Authors: Li JQ, Qiu YL, Gong JY, Dou LM, Lu Y, Knisely AS, Zhang MH, Luan WS, Wang JS

Abstract
BACKGROUND: Underlying causes in Chinese children with recurrent acute liver failure (RALF), including liver crises less than full acute liver failure, are incompletely understood. We sought to address this by searching for genes mutated in such children.
METHODS: Five unrelated Chinese boys presenting between 2012 and 2015 with RALF of unexplained etiology were studied. Results of whole exome sequencing were screened for mutations in candidate genes. Mutations were verified in patients and their family members by Sanger sequencing. All 5 boys underwent liver biopsy.
RESULTS: NBAS was the only candidate gene mutated in more than one patient (biallelic mutations, 3 of 5 patients; 5 separate mutations). All NBAS mutations were novel and predictedly pathogenic (frameshift insertion mutation c.6611_6612insCA, missense mutations c.2407G > A and c.3596G > A, nonsense mutation c.586C > T, and splicing-site mutation c.5389 + 1G > T). Of these mutations, 3 lay in distal (C-terminal) regions of NBAS, a novel distribution. Unlike the 2 patients without NBAS mutations, the 3 patients with confirmed NBAS mutations all suffered from a febrile illness before each episode of liver crisis (fever-related RALF), with markedly elevated alanine aminotransferase and aspartate aminotransferase activities 24-72 h after elevation of body temperature, succeeded by severe coagulopathy and mild to moderate jaundice.
CONCLUSIONS: As in other countries, so too in China; NBAS disease is a major cause of fever-related RALF in children. The mutation spectrum of NBAS in Chinese children seems different from that described in other populations.

PMID: 28629372 [PubMed - in process]

Genomic analysis of melanoma evolution following a 30 year disease-free interval.

J Cutan Pathol. 2017 Jun 19;:

Authors: Miller JJ, Lofgren KA, Hughes SR, Cash SE, Kenny PA

Abstract
Ultra-late melanoma recurrence is infrequent, poorly understood and, in most cases, difficult to unambiguously distinguish from a new primary melanoma. We identified a patient with a second melanoma diagnosed after a 30 year disease-free interval, and sought to determine if this new lesion was a recurrence of the original melanoma. Here we report the genomic sequence analysis of the exomes of two melanoma lesions isolated from the same individual in 1985 and 2015, and their comparison to each other and to the germline DNA of the patient. Identification of many shared somatic mutations between these lesions prove a lineal relationship spanning 30 years. Unlike prior reports of ultra-late melanoma recurrence, the availability of the original tumor and the use of comprehensive genomic analysis allowed us to confirm that the second lesion is truly a recurrence. We demonstrate the acquisition of numerous additional mutations during the three decade asymptomatic period. These data highlight the low but very long-lasting risk of recurrence in this patient population.

PMID: 28628281 [PubMed - as supplied by publisher]

Clinical Applicability of Whole-Exome Sequencing Exemplified by a Study in Young Adults with the Advanced Cryptogenic Cholestatic Liver Diseases.

Gastroenterol Res Pract. 2017;2017:4761962

Authors: Kulecka M, Habior A, Paziewska A, Goryca K, Dąbrowska M, Ambrozkiewicz F, Walewska-Zielecka B, Gabriel A, Mikula M, Ostrowski J

Abstract
BACKGROUND: The proper use of new medical tests in clinical practice requires the establishment of their value and range of diagnostic usefulness. While whole-exome sequencing (WES) has already entered the medical practice, recognizing its diagnostic usefulness in multifactorial diseases has not yet been achieved.
AIMS: The objective of this study was to establish usability of WES in determining genetic background of chronic cholestatic liver disease (CLD) in young patients.
METHODS: WES was performed on six young patients (between 17 and 22 years old) with advanced fibrosis or cirrhosis due to CLD and their immediate families. Sequencing was performed on an Ion Proton sequencer.
RESULTS: On average, 19,673 variants were identified, of which from 7 to 14 variants of an individual were nonsynonymous, homozygous, recessively inherited, and considered in silico as pathogenic. Although monogenic cause of CLD has not been determined, several heterozygous rare variants and polymorphisms were uncovered in genes previously known to be associated with CLD, including ATP8B1, ABCB11, RXRA, and ABCC4, indicative of multifactorial genetic background.
CONCLUSIONS: WES is a potentially useful diagnostic tool in determining genetic background of multifactorial diseases, but its main limitation results from the lack of opportunities for direct linkage between the uncovered genetic variants and molecular mechanisms of disease.

PMID: 28626473 [PubMed - in process]

A homozygous founder mutation in TRAPPC6B associates with a neurodevelopmental disorder characterised by microcephaly, epilepsy and autistic features.

J Med Genet. 2017 Jun 16;:

Authors: Marin-Valencia I, Novarino G, Johansen A, Rosti B, Issa MY, Musaev D, Bhat G, Scott E, Silhavy JL, Stanley V, Rosti RO, Gleeson JW, Imam FB, Zaki MS, Gleeson JG

Abstract
BACKGROUND: Transport protein particle (TRAPP) is a multisubunit complex that regulates membrane trafficking through the Golgi apparatus. The clinical phenotype associated with mutations in various TRAPP subunits has allowed elucidation of their functions in specific tissues. The role of some subunits in human disease, however, has not been fully established, and their functions remain uncertain.
OBJECTIVE: We aimed to expand the range of neurodevelopmental disorders associated with mutations in TRAPP subunits by exome sequencing of consanguineous families.
METHODS: Linkage and homozygosity mapping and candidate gene analysis were used to identify homozygous mutations in families. Patient fibroblasts were used to study splicing defect and zebrafish to model the disease.
RESULTS: We identified six individuals from three unrelated families with a founder homozygous splice mutation in TRAPPC6B, encoding a core subunit of the complex TRAPP I. Patients manifested a neurodevelopmental disorder characterised by microcephaly, epilepsy and autistic features, and showed splicing defect. Zebrafish trappc6b morphants replicated the human phenotype, displaying decreased head size and neuronal hyperexcitability, leading to a lower seizure threshold.
CONCLUSION: This study provides clinical and functional evidence of the role of TRAPPC6B in brain development and function.

PMID: 28626029 [PubMed - as supplied by publisher]

Tracking the Evolution of Non-Small-Cell Lung Cancer.

N Engl J Med. 2017 06 01;376(22):2109-2121

Authors: Jamal-Hanjani M, Wilson GA, McGranahan N, Birkbak NJ, Watkins TBK, Veeriah S, Shafi S, Johnson DH, Mitter R, Rosenthal R, Salm M, Horswell S, Escudero M, Matthews N, Rowan A, Chambers T, Moore DA, Turajlic S, Xu H, Lee SM, Forster MD, Ahmad T, Hiley CT, Abbosh C, Falzon M, Borg E, Marafioti T, Lawrence D, Hayward M, Kolvekar S, Panagiotopoulos N, Janes SM, Thakrar R, Ahmed A, Blackhall F, Summers Y, Shah R, Joseph L, Quinn AM, Crosbie PA, Naidu B, Middleton G, Langman G, Trotter S, Nicolson M, Remmen H, Kerr K, Chetty M, Gomersall L, Fennell DA, Nakas A, Rathinam S, Anand G, Khan S, Russell P, Ezhil V, Ismail B, Irvin-Sellers M, Prakash V, Lester JF, Kornaszewska M, Attanoos R, Adams H, Davies H, Dentro S, Taniere P, O'Sullivan B, Lowe HL, Hartley JA, Iles N, Bell H, Ngai Y, Shaw JA, Herrero J, Szallasi Z, Schwarz RF, Stewart A, Quezada SA, Le Quesne J, Van Loo P, Dive C, Hackshaw A, Swanton C, TRACERx Consortium

Abstract
BACKGROUND: Among patients with non-small-cell lung cancer (NSCLC), data on intratumor heterogeneity and cancer genome evolution have been limited to small retrospective cohorts. We wanted to prospectively investigate intratumor heterogeneity in relation to clinical outcome and to determine the clonal nature of driver events and evolutionary processes in early-stage NSCLC.
METHODS: In this prospective cohort study, we performed multiregion whole-exome sequencing on 100 early-stage NSCLC tumors that had been resected before systemic therapy. We sequenced and analyzed 327 tumor regions to define evolutionary histories, obtain a census of clonal and subclonal events, and assess the relationship between intratumor heterogeneity and recurrence-free survival.
RESULTS: We observed widespread intratumor heterogeneity for both somatic copy-number alterations and mutations. Driver mutations in EGFR, MET, BRAF, and TP53 were almost always clonal. However, heterogeneous driver alterations that occurred later in evolution were found in more than 75% of the tumors and were common in PIK3CA and NF1 and in genes that are involved in chromatin modification and DNA damage response and repair. Genome doubling and ongoing dynamic chromosomal instability were associated with intratumor heterogeneity and resulted in parallel evolution of driver somatic copy-number alterations, including amplifications in CDK4, FOXA1, and BCL11A. Elevated copy-number heterogeneity was associated with an increased risk of recurrence or death (hazard ratio, 4.9; P=4.4×10(-4)), which remained significant in multivariate analysis.
CONCLUSIONS: Intratumor heterogeneity mediated through chromosome instability was associated with an increased risk of recurrence or death, a finding that supports the potential value of chromosome instability as a prognostic predictor. (Funded by Cancer Research UK and others; TRACERx ClinicalTrials.gov number, NCT01888601 .).

PMID: 28445112 [PubMed - indexed for MEDLINE]